Analysis of catalytic determinants of diaminopimelate and ornithine decarboxylases using alternate substrates

Emily J. Fogle, Michael D. Toney

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Diaminopimelate decarboxylase (DAPDC) and ornithine decarboxylase (ODC) are pyridoxal 5′-phosphate dependent enzymes that are critical to microbial growth and pathogenicity. The latter is the target of drugs that cure African sleeping sickness, while the former is an attractive target for antibacterials. These two enzymes share the (β/α)8 (i.e., TIM barrel) fold with alanine racemase, another pyridoxal 5′-phosphate dependent enzyme critical to bacterial survival. The active site structural homology between DAPDC and ODC is striking even though DAPDC catalyzes the decarboxylation of a D stereocenter with inversion of configuration and ODC catalyzes the decarboxylation of an L stereocenter with retention of configuration. Here, the structural and mechanistic bases of these interesting properties are explored using reactions of alternate substrates with both enzymes. It is concluded that simple binding determinants do not control the observed stereochemical specificities for decarboxylation, and a concerted decarboxylation/proton transfer at Cα of the D stereocenter of diaminopimelate is a possible mechanism for the observed specificity with DAPDC.

Original languageEnglish (US)
Pages (from-to)1113-1119
Number of pages7
JournalBiochimica et Biophysica Acta - Proteins and Proteomics
Volume1814
Issue number9
DOIs
StatePublished - Sep 2011

Fingerprint

Decarboxylation
Ornithine Decarboxylase
Carboxy-Lyases
Pyridoxal Phosphate
Substrates
Enzymes
Alanine Racemase
African Trypanosomiasis
Proton transfer
Virulence
Protons
Catalytic Domain
Growth
Pharmaceutical Preparations

Keywords

  • Decarboxylase
  • Decarboxylation
  • Enzyme mechanisms
  • Pyridoxal 5′phosphate
  • Reaction specificity
  • TIM barrel

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Analytical Chemistry
  • Molecular Biology

Cite this

Analysis of catalytic determinants of diaminopimelate and ornithine decarboxylases using alternate substrates. / Fogle, Emily J.; Toney, Michael D.

In: Biochimica et Biophysica Acta - Proteins and Proteomics, Vol. 1814, No. 9, 09.2011, p. 1113-1119.

Research output: Contribution to journalArticle

@article{4f3ad45eedce4034a00880ff3973c5b7,
title = "Analysis of catalytic determinants of diaminopimelate and ornithine decarboxylases using alternate substrates",
abstract = "Diaminopimelate decarboxylase (DAPDC) and ornithine decarboxylase (ODC) are pyridoxal 5′-phosphate dependent enzymes that are critical to microbial growth and pathogenicity. The latter is the target of drugs that cure African sleeping sickness, while the former is an attractive target for antibacterials. These two enzymes share the (β/α)8 (i.e., TIM barrel) fold with alanine racemase, another pyridoxal 5′-phosphate dependent enzyme critical to bacterial survival. The active site structural homology between DAPDC and ODC is striking even though DAPDC catalyzes the decarboxylation of a D stereocenter with inversion of configuration and ODC catalyzes the decarboxylation of an L stereocenter with retention of configuration. Here, the structural and mechanistic bases of these interesting properties are explored using reactions of alternate substrates with both enzymes. It is concluded that simple binding determinants do not control the observed stereochemical specificities for decarboxylation, and a concerted decarboxylation/proton transfer at Cα of the D stereocenter of diaminopimelate is a possible mechanism for the observed specificity with DAPDC.",
keywords = "Decarboxylase, Decarboxylation, Enzyme mechanisms, Pyridoxal 5′phosphate, Reaction specificity, TIM barrel",
author = "Fogle, {Emily J.} and Toney, {Michael D.}",
year = "2011",
month = "9",
doi = "10.1016/j.bbapap.2011.05.014",
language = "English (US)",
volume = "1814",
pages = "1113--1119",
journal = "Biochimica et Biophysica Acta - Proteins and Proteomics",
issn = "1570-9639",
publisher = "Elsevier",
number = "9",

}

TY - JOUR

T1 - Analysis of catalytic determinants of diaminopimelate and ornithine decarboxylases using alternate substrates

AU - Fogle, Emily J.

AU - Toney, Michael D.

PY - 2011/9

Y1 - 2011/9

N2 - Diaminopimelate decarboxylase (DAPDC) and ornithine decarboxylase (ODC) are pyridoxal 5′-phosphate dependent enzymes that are critical to microbial growth and pathogenicity. The latter is the target of drugs that cure African sleeping sickness, while the former is an attractive target for antibacterials. These two enzymes share the (β/α)8 (i.e., TIM barrel) fold with alanine racemase, another pyridoxal 5′-phosphate dependent enzyme critical to bacterial survival. The active site structural homology between DAPDC and ODC is striking even though DAPDC catalyzes the decarboxylation of a D stereocenter with inversion of configuration and ODC catalyzes the decarboxylation of an L stereocenter with retention of configuration. Here, the structural and mechanistic bases of these interesting properties are explored using reactions of alternate substrates with both enzymes. It is concluded that simple binding determinants do not control the observed stereochemical specificities for decarboxylation, and a concerted decarboxylation/proton transfer at Cα of the D stereocenter of diaminopimelate is a possible mechanism for the observed specificity with DAPDC.

AB - Diaminopimelate decarboxylase (DAPDC) and ornithine decarboxylase (ODC) are pyridoxal 5′-phosphate dependent enzymes that are critical to microbial growth and pathogenicity. The latter is the target of drugs that cure African sleeping sickness, while the former is an attractive target for antibacterials. These two enzymes share the (β/α)8 (i.e., TIM barrel) fold with alanine racemase, another pyridoxal 5′-phosphate dependent enzyme critical to bacterial survival. The active site structural homology between DAPDC and ODC is striking even though DAPDC catalyzes the decarboxylation of a D stereocenter with inversion of configuration and ODC catalyzes the decarboxylation of an L stereocenter with retention of configuration. Here, the structural and mechanistic bases of these interesting properties are explored using reactions of alternate substrates with both enzymes. It is concluded that simple binding determinants do not control the observed stereochemical specificities for decarboxylation, and a concerted decarboxylation/proton transfer at Cα of the D stereocenter of diaminopimelate is a possible mechanism for the observed specificity with DAPDC.

KW - Decarboxylase

KW - Decarboxylation

KW - Enzyme mechanisms

KW - Pyridoxal 5′phosphate

KW - Reaction specificity

KW - TIM barrel

UR - http://www.scopus.com/inward/record.url?scp=79959746255&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79959746255&partnerID=8YFLogxK

U2 - 10.1016/j.bbapap.2011.05.014

DO - 10.1016/j.bbapap.2011.05.014

M3 - Article

VL - 1814

SP - 1113

EP - 1119

JO - Biochimica et Biophysica Acta - Proteins and Proteomics

JF - Biochimica et Biophysica Acta - Proteins and Proteomics

SN - 1570-9639

IS - 9

ER -